AlCl3 as a powerful catalyst for the one-pot preparation of 1,1,3-triheteroaryl compounds

Article abstract of DOI:10.1016/j.tetlet.2009.10.127

A general and efficient procedure for the synthesis of 1,1,3-triheteroaryl compounds in good to excellent yield at room temperature is developed. The reaction proceeds via mixed Michael and Friedel-Crafts reactions of α,β-enals or α,β-enones and indoles, 2-methylfuran or 2-methylthiophene in the presence of a catalytic amount of AlCl₃.

Full text of DOI:10.1016/j.tetlet.2009.10.127

Tetrahedron Letters 51 (2010) 264–268
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AlCl3 as a powerful catalyst for the one-pot preparation
of 1,1,3-triheteroaryl compounds
b,
b
Morteza Shiri a, , Mohammad Ali Zolfigol , Roya Ayazi-Nasrabadi
*
*
a Department of Chemistry, College of Science, Alzahra University, Vanak 1993891176, Tehran, Iran
b Faculty of Chemistry, Bu-Ali Sina University, 6517838683 Hamedan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A general and efficient procedure for the synthesis of 1,1,3-triheteroaryl compounds in good to excellent
yield at room temperature is developed. The reaction proceeds via mixed Michael and Friedel–Crafts
Received 6 August 2009
Revised 21 October 2009
Accepted 28 October 2009
Available online 30 October 2009
reactions of
a,b-enals or a,b-enones and indoles, 2-methylfuran or 2-methylthiophene in the presence
of a catalytic amount of AlCl3.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts reaction
Michael addition
Indoles
Heteroaryls
a,b-Unsaturated carbonyl compounds
The Michael reaction is generally regarded as one of the most
solvent. In initial experiments, indole 1a and crotonaldehyde (2a)
were used as model substrates to evaluate suitable reaction condi-
tions for the preparation of tris-indole 3a (Table 1). A wide range of
Brönsted and Lewis acids were examined in acetonitrile as solvent.
Protic acids such as silica sulfuric acid (SSA)11 (Table 1, entry 12),
and the metal hydrogen sulfates12 such as Al(HSO4)3, NaHSO4ÁH2O
and Zr(HSO4)4 (Table 1, entries 13–15) promoted the reaction in
70–97% yields after 4.5 to 24 h. It was also found that Lewis acids
such as Bi(NO3)3, Ni(NO3)3, Cd(NO3)3, LiOTf, ZnCl2, and CoCl2Á6H2O
were not active in this condensation since no product was
observed even after stirring for 24 h (Table 1, entries 9–11 and
19–21). Under the same conditions, AuCl3 and SbCl3 gave 3a in
70% yield after 12 h, and 94% yield after 3.5 h, respectively, whilst
I2 and CAN gave 95% and 90% yields of product after 24 h and 3.5 h,
respectively (Table 1, entries 4 and 5). Although this reaction pro-
ceeded smoothly in the presence of several of the tested catalysts,
it was felt that an improved method should still be sought. Surpris-
ingly, the reaction to form 1,1,3-tri(1H-indol-3-yl)butane (3a) in
96% yield was completed in 8 min when only 10 mol % AlCl3 was
used as the catalyst (Table 1, entry 1).
efficient carbon–carbon bond forming reactions, and studies
concerning this reaction have played an important role in the
development of modern synthetic organic chemistry.1 The
Friedel–Crafts reaction is also another method for the formation
of new C–C bonds and has been widely utilized from bench-top
experiments to industrial processes.2 The domino Michael addition
of aryl compounds to enals or enones followed by the Friedel–
Crafts reaction leads to a series of naturally occurring 1,1,3-triaryl
systems which are an important class of bioactive metabolites. For
example, tris-indole 3a was isolated as a racemate from the bacte-
rium Vibrio parahaemolyticus.3 Also, Lee et al. found that 1,1,3-
tri(3-indolyl)cyclohexane inhibits the growth of lung cancer cells
of xenograft models.4
However, these one-pot methods usually make use of expensive
catalysts such as AuCl3,5 and Zr(OTf)4,6 the hazardous catalyst
SbCl3,7 cerium ammonium nitrate (CAN) and I2.8
Various active heterocycles, especially indoles are important
building blocks for biologically active compounds.9 In our efforts
to develop a new method for the synthesis of indolyl compounds,10
we were interested in the catalytic preparation of 1,1,3-triindolyls
from enals or enones and indoles.
5
7
A wide range of solvents were tested to investigate the effect of
solvent on the reaction of indole and crotonaldehyde catalysed by
AlCl3 (Table 2). The reaction was completed in AcOH in 20 min
affording a 97% yield of 3a (Table 2, entry 2). In the absence of
AlCl3, 3a was obtained in only 70% yield using AcOH as a solvent
even after 12 h (Table 2, entry 3). When acetone was used as the
solvent, 2,2-bis(indolyl-3-yl)propane was produced in 25% yield
as a by-product (Table 2, entry 4). In most of the other solvents
Herein, we report on such a process, as well as the appropriate
selection of reaction parameters such as type of catalyst and
* Corresponding authors. Fax: +98 21 88041344 (M.S.); +98 811 8257407
(M.A.Z.).
E-mail addresses: mshiri@alzahra.ac.ir (M. Shiri), zolfi@basu.ac.ir (M.A. Zolfigol).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.127

M. Shiri et al. / Tetrahedron Letters 51 (2010) 264–268
265
Table 1
Table 2
Effect of catalyst on the preparation of 3a from indole (1a) and crotonaldehyde (2a)
Effect of solvent on the preparation of 3a from indole and crotonaldehyde in the
presence of AlCl3
H
N
Entry
Solvent
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
CH3CN
AcOH
8 min
20 min
12
12
20
12
12
24
12
96
97
50
71
92
93
91
0
cat. (10 mol%)
+
O
N
AcOHa
Acetoneb
CH2Cl2
CHCl3
CCl4
NH
CH3CN, rt
H
N
H
1a
2a
3a
n-Hexane
EtOH
MeOH
THF
92
84
88
Entry
Catalyst
Time (h)
Isolated yield (%)
10
11
12
12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
AlCl3
8 min
12
3.5
24
3.5
24
4
96
70
94
95
90
94
98
98
0
AuCl3,5
a
SbCl3,7
Without AlCl3.
25% of 2,2-bis(indol-3-yl)propane was isolated.
b
I2
CAN
FeCl3Á6H2O
Fe(NO3)3Á9H2O
Cr(NO3)3
Bi(NO3)3
Ni(NO3)3
Cd(NO3)3
SSA
Al(HSO4)3
NaHSO4ÁH2O
Zr(HSO4)4
ZrCOCl2Á8H2O
ZrCl4
4
24
24
24
12.5
4.5
24
7
1.5
4.5
6.5
24
24
24
Cl-
O
0
0
indole (2 equiv.)
AlCl2
indole
Cl
HN
97
89
88
70
97
94
89
0
3a
O
H2O
Al
Cl
Cl-
Zr(NO3)4
LiOTf
ZnCl2
A
0
0
AlCl3
CoCl2Á6H2O
O
Scheme 1. A proposed mechanism for the reaction of 1a and 2a catalyzed by AlCl3.
Table 3
The reaction of heteroaryls 1 and
a,b-enals or enones 2 in the presence of AlCl3 in CH3CN
Entry Heteroaryl 1
a,b-Enal or enone 2
1,1,3-Triheteroaryl 3
Time (min)
Isolated yield (%)
O
H
N
2b
1
1a
13
90
NH
N
H
3b
3c
3d
N
N
1b
2
2b
10
88
N
N
H
N
N
H
1c
3
2b
10
97
NH
N
H
(continued on next page)

266
M. Shiri et al. / Tetrahedron Letters 51 (2010) 264–268
Table 3 (continued)
Entry
Heteroaryl 1
a,b-Enal or enone 2
1,1,3-Triheteroaryl 3
Time (min)
Isolated yield (%)
Br
H
N
N
H
Br
1d
NH
Br
4
2b
4 h
96
N
H
Br
3e
O
O
O
1e
5
6
2b
2b
4 h
81
85
O
3f
S
S
S
1f
S
4 h
3g
N
7
1b
2a
5
97
N
N
3h
H
N
8
1c
2a
5
98
NH
N
H
3i
H
N
Br
NH
Br
9
1d
2a
2.5 h
98
N
H
Br
3j
O
O
O
10
1e
2a
4 h
92
3k
O
H
N
2c
11
1a
1.3 h
96
NH
N
H
3l

M. Shiri et al. / Tetrahedron Letters 51 (2010) 264–268
267
Table 3 (continued)
Entry
Heteroaryl 1
a,b-Enal or enone 2
1,1,3-Triheteroaryl 3
Time (min)
Isolated yield (%)
N
12
1b
2c
10
90
N
N
3m
H
N
13
1c
2c
5
97
NH
N
H
3n
H
N
Br
NH
Br
14
1d
2c
3.25 h
97
N
H
Br
3o
O
H
N
2d
15
1a
30
100
NH
N
H
3p
3q
N
N
16
1b
2d
20
89
N
O
O
17
18
19
1a
1b
1c
15
12 h
5
92
70
2f
N
H
3r
N
N
2f
2f
N
3s
O
99
N
H
3t
(continued on next page)

268
M. Shiri et al. / Tetrahedron Letters 51 (2010) 264–268
Table 3 (continued)
Entry
Heteroaryl 1
a,b-Enal or enone 2
1,1,3-Triheteroaryl 3
Time (min)
Isolated yield (%)
O
Br
20
1d
2f
7
100
N
H
3u
(except for n-hexane) the reaction proceeded smoothly. These
experiments revealed that CH3CN was the best solvent for this
reaction (Table 2, entry 1).
Supplementary data
Supplementary data (data for other products and copies of spec-
tra) associated with this article can be found, in the online version,
at doi:10.1016/j.tetlet.2009.10.127.
A plausible mechanistic pathway is shown in Scheme 1.
Although we do not have additional evidence for this, we hypoth-
esize that rapid formation of 3a may be due to the initial formation
of intermediate A from AlCl3 and 2a. Next, indole is added to labile
intermediate A to yield the corresponding Michael adduct. Subse-
quent Friedel–Crafts reaction of indole with the aldehydes (twice)
gives 3a (Scheme 1). It is thought that AlCl3 promotes the reaction
by increasing the electrophilic character of the enal.
References and notes
1. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon
Press: Oxford, 1992.
2. (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S.. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3,
pp 293–339. Chapter 1.8; (b) Meima, G. R.; Lee, G. S.; Garces, J. M. In Friedel–
Crafts Alkylation; Sheldon, R. A., Bekkum, H., Eds.; Wiley-VCH: New York, 2001;
pp 151–160.
3. Veluri, R.; Oka, I.; Wagner-Dobler, I.; Laatsch, H. J. Nat. Prod. 2003, 66, 1520–1523.
4. Lee, C. H.; Yao, C. F.; Huang, S. M.; Ko, S.; Tan, Y. H.; Lee-Chen, G. J.; Wang, Y. C.
Cancer 2008, 113, 815–825.
Next, the scope of this catalytic tandem Michael and Friedel–
Crafts alkylation was broadened to include the reaction between
active heteroaryls with a,b-enals and enones, under the optimized
reaction conditions (Table 3).13 A number of indoles 1a–d were uti-
lized in the reaction with acrolein (2b) catalyzed by AlCl3 in CH3CN.
The reaction afforded the corresponding 1,1,3-triindolyl products
3b–e in high yields (Table 3, entries 1–4).
5. Nair, V.; Vidya, N.; Abhilash, K. G. Tetrahedron Lett. 2006, 47, 2871–2873.
6. Shi, M.; Cui, S. C.; Li, Q. J. Tetrahedron 2004, 60, 6679–6684.
7. Kundu, P.; Maiti, G. Indian J. Chem. 2008, 47B, 1402–1406.
It was found that acrolein also reacted efficiently with other
heterocycles such as 2-methylfuran and 2-methylthiophene (Table
3, entries 5 and 6). Reaction of other enals such as crotonaldehyde
(2a), trans-2-pentanal (2c) and trans-2-hexanal (2d) with heterocy-
cles 1a–e, gave a library of 1,1,3-triheteroaryl compounds in high
yields (Table 3, entries 7–16).
Reaction of methyl vinyl ketone with indole, 2-methylindole or
5-bromoindole under the same conditions gave only the Michael
products (Table 3, entries 17, 19 and 20) even after stirring for
12 h. However, with 1-methylindole (1b) the corresponding tris-
indolyl product 3s was obtained (Table 3, entry 18).
8. Ko, S.; Lin, C.; Tu, Z.; Wang, Y. F.; Wang, C. C.; Yao, C. F. Tetrahedron Lett. 2006,
47, 487–492.
9. (a) Taylor, E. C., Series ed.. In The Chemistry of Heterocyclic Compounds; Saxton, J.
E., Ed.; Wiley-Interscience: New York, 1983; Vol. 25,. Part 4 (b) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045; (c) Gilchrist, T. A. J. Chem. Soc., Perkin
Trans. 1 1998, 615; (d) Nobuyoshi, A.; Akihiko, O.; Chikara, M.; Tatsuya, T.;
Masami, O.; Hiromitsu, S. J. Med. Chem. 1999, 42, 2946; (e) Elguero, J.. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon Press: New York, 1984; Vol. 5, p 167.
10. (a) Zolfigol, M. A.; Salehi, P.; Shiri, M.; Tanbakouchian, Z. Catal. Commun. 2007,
8, 173–178; (b) Zolfigol, M. A.; Salehi, P.; Shiri, M. Phosphorus, Sulfur Silicon
2004, 179, 2273–2277; (c) Zolfigol, M. A.; Salehi, P.; Shiri, M.; Sayadi, A.; Abdoli,
A.; Keypoor, H.; Rezaeivalla, M.; Niknam, K.; Kolvari, E. Mol. Divers. 2008, 12,
203–207; (d) Niknam, K.; Zolfigol, M. A.; Sadabadi, T.; Nejati, A. J. Iran Chem.
Soc. 2006, 3, 318–322.
In conclusion, we have developed a novel and highly efficient
method for preparing a library of 1,1,3-triindolyl compounds in
excellent yields through the tandem Michael addition and Fri-
11. (a) Salehi, P.; Zolfigol, M. A.; Shirini, F.; Baghbanzadeh, M. Curr. Org. Chem.
2006, 10, 2171–2189; (b) Zolfigol, M. A. Tetrahedron 2001, 57, 9509–9511.
12. Shirini, F.; Zolfigol, M. A.; Salehi, P.; Abedini, M. Curr. Org. Chem. 2008, 12, 183–
202.
edel–Crafts reaction of
a,b-unsaturated aldehydes or ketones and
13. Typical experimental procedure for the preparation of 3a: To a stirring solution of
crotonaldehyde (1 mmol) and indole (4 mmol) in CH3CN (5 mL), AlCl3
(0.1 mmol) was added at room temperature. After 8 min, the solvent was
evaporated under reduced pressure. The product was purified by flash column
chromatography using n-hexane–ethyl acetate (8:2) as eluent to give 3a5 in 96%
yield; mp 114–116 °C. FT-IR (KBr): 3409, 3053, 2956, 2924, 2867, 1617, 1546,
indoles, in the presence of a catalytic amount of AlCl3 in CH3CN.
In addition, this system also works well with 2-methylfuran and
2-methylthiophene. Further studies in this area are ongoing.
Acknowledgements
1455, 1337, 1221, 1094, 1010, 742 cmÀ1 1H NMR (300 MHz, CDCl3), d (ppm):
.
1.45 (3H, d, J = 6.8 Hz), 2.50 (1H, m), 2.73 (1H, m), 3.10 (1H, m), 4.58 (1H, t,
J = 7.3 Hz), 6.85 (1H, s), 6.88 (1H, s), 6.94 (1H, s), 7.01 (3H, m), 7.18 (3H, m), 7.28
(3H, m), 7.47 (2H, t, J = 7.8 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.75 (2H, s, N–H, D2O
exchangeable), 7.80 (1H, s, N–H, D2O exchangeable). 13C NMR (75 MHz, CDCl3), d
(ppm): 21.9, 29.94, 31.9, 43.6, 111.0, 111.12, 111.16, 118.90, 118.97, 119.7,
119.82, 120.2, 120.3, 121.5, 121.7, 122.5, 126.8, 127.0, 136.52, 136.56, 136.62.
We thank Alzahra University, Bu-Ali Sina University and Elite
national Foundation (Iran) for financial support to our research
group. Professor H. G. Kruger of UKZN in South Africa is acknowl-
edged for proof-reading the Letter.